The present invention relates to a method for the direct halogenation, especially the iodination, of aroma- tic compounds.

Aryl iodides have found widespread use in organic chemistry and have been utilised for more than a hundred years for organic syntheses, for example the Ull an reac¬ tion (Fanta, P.E. Synthesis 1974, 9) and the reaction ac- cording to Heck (Heck, R.F. Org. React (NY) 1982, 27, 345). Polyiodinated, especially triiodinated, aromatic compounds are widely used as X-ray contrast agents.

The iodination of aromatic compounds may be carried out by direct or indirect iodination. The indirect method comprise several different synthesis steps and therefore are both complicated and expensive. The direct methods in which carbon-iodine bonds are formed directly, are pre¬ ferred, but in the absence of a simple and reliable tech¬ nique they have so far not been extensively used. Direct iodination of aromatic compounds may be car¬ ried out by adding iodine in the presence of a Lewis acid, a hydrogen iodide trap or, most common, an oxidising agent.

If an oxidising agent is used, iodination occurs schematically according to the formula

ox + 0.5 ly + ArH > Arl + H + red

and a large number of oxidising agents have been used for carrying this conversion into effect. HN0 ₃ /H,,S0. according to the Tronov-Novikov method (Merkushev, E.V. Russ. Chem.

Rev. (English translation) 1984, 53, 583) have been widely used, but also HI0 ₃ /H ₂ S0 ₄ , KMnO., SbCl ₅ , metal ions (for example Co( III), Ce(IV), Cu(II), V(V)), CH ₃ COOH, C-H,-I(OCOCF)_ and anodic oxidation have been applied with b D acceptable results. However, some of these methods are disadvantageous in that they require drastic reaction con-

ditions, such as more or less obnoxious oxidising."agents and/or high temperatures. All of the above-mentioned methods suffer from the disadvantage that large (i.e. stoichiometric) amounts of oxidising agent are necessary. 5 An agent frequently used in the direct iodination of aromatic compounds is IC1 ₃ which, however, is disadvan¬ tageous in that it produces chlorine gas. Furthermore, IC1_ must be produced itself, and this means an additional step. 0 It is the object of this invention to provide a simple and economic method for the direct halogenation of aromatic compounds.

A further object of the invention is to provide a method that can be carried out at room temperature without 5 aggressive oxidising agents and without excessive amounts of reagent.

The method according to the invention is character¬ ised in that a mixture of a halogen compound, and an aro¬ matic compound is subjected to oxygen at room temperature 0 and. in the presence of catalytic amounts of a lower nitro¬ gen oxide compound convertible into NO .

The reaction may be indicated by the following sche¬ matic formula

+ ₅ ArH + I ^" + H ⁺ + 0.5 0 ₂ — > Arl + H ₂ 0

Schematically, the reaction is carried out by adding to a reaction vessel and under agitation a halogen com¬ pound, such as NH.I, and an aromatic compound in an acid ₀ medium, such as CF^COOH/CH.-Cl.-.. The mixture is exposed to oxygen, and a catalytic amount of a lower nitrogen oxide compound, for example NOBF., convertible into NO , is added.

The oxygen source preferably is air or pure oxygen,

-,-. but any other gaseous mixture containing oxygen can be used. The lower nitrogen oxide compound utilised by the present invention is added in catalytic, i.e. small

amounts. The exact amount required depends primarily on the scale on which the method is carried out.

For low-scale production a larger amount of nitrogen oxide compound is required than for production on an in- dustrial scale because higher losses are encountered in low-scale production. Nevertheless, the amounts involved are always small catalytic amounts. The amount of nitrogen oxide compound utilised by the present invention normally amounts to at most about 5 mol%, in relation to the aro- matic compound, and for large scale production the amounts are preferably at most 3-4 mol%, and most preferred 1-2 mol%. For experiments on a laboratory scale, up to about 5 mol% nitrogen oxide compound may be required, while 1-2 mol% are frequently sufficient for large-scale industrial production.

A large amount of different acid solvents or solvent mixtures can be used for the method according to the in¬ vention, for example CH ₃ C00H, CH ₂ C1 ₂ , CF ₃ C00H, CH ₃ S0 ₃ H, CC1 ₃ C00H, H ₂ S0., and mixtures thereof. The type of the acid medium is not critical; the im¬ portant thing is that H ions are available. The most fre¬ quent selection criteria are economy and availability.

By varying the reaction time, the selection of acid, the amount of acid and, for a mixture, the ratio of the acids included, aromatic compounds with as different reac¬ tivity as the halobenzenes and thiophene, can be satis¬ factorily iodinated. It appears from Tables 1 and 5 that it is possible, by using the method of the application and by varying the solvent system, to iodinate aromatic com- pounds of highly different reactivity, but not benzotri- fluoride which has a very low reactivity ( see Table 1 ) . The difficulties encountered in the iodination of reactive aromatics in an oxidising medium are clearly apparent if 1-methoxynaphthalene is used as substrate (see Table 1, last entry). With the acid mixture CFgCOOH:CH ₂ C1 ₂ in a ratio of 3:1, substantially no iodination was obtained, whereas the same substrate under milder reaction condi-

tions (CF ₃ C00H:CH ₃ C00H 1:10) could be iodinated with a yield of 83% (see Table 5) . Iodination of thiophene in undiluted CF-COOH gave a relatively insignificant yield, while iodination in CF_C00H/CH ₂ C1 ₂ (Table 1 ) or CFgCOOH/CH^COOH gave highly satisfactory yields. Pyrene is an especially difficult compound. This compound which nor¬ mally is highly reactive, forms a molecular complex with I„, and so far there has been no method for direct mono- iodination of this compound. However, the method according to the invention, when carried out under the conditions as indicated in Table 6, gave 1-iodopyrene in a yield of 36%.

Table 4 indicates examples of different acid solvent mixtures useful in connection with the method according to the invention. Preferred solvent systems are CF-COOH/

CH ₃ COOH and CF ₃ C00H/CH ₂ C1 ₂ where the amount of trifluoro- acetic acid is at least 10% of the total amount of sol¬ vent.

No appreciable change occurred when CF^COOH was re- placed by CH ₃ S0.,H, CC1...C00H and CF ₃ C00H:CH ₃ C00H 1:3, but CH.-C00H alone gave a far slower reaction. However, CH-COOH and CH^Cl- can be used with excellent results as a diluent for CF ₃ C00H.

Table 2 illustrates the yield upon iodination of a number of different aromatic compounds.

A number of lower nitrogen oxide compounds convert¬ ible into NO can be used in the method of the present in¬ vention, and excellent results were obtained with both N0BF ₄ and N0 ₂ , NaN0 ₂ and NaNO,. Table 7 illustrates the catalytic effect of a number of nitrogen oxides. NaN0 ₃ was found to be an efficient ca¬ talyst for iodination of mesitylene, .and also toluene could be satisfactorily iodinated after addition of H ₂ S0.. Examples of useful hydrogen sources are NH.X wherein X is I, Br or Cl, Nal, KI, Bu ₄ NI and I ₂ - Table 6 illu¬ strates experiments made with I„ and H ₄ I, respectively.

Table 3 indicates the results of experiments carried out with, respectively, pure oxygen and air as oxygen source during iodination of p-xylene.

Experiments were carried out both on a small scale and on a large scale, with excellent results. The aryl iodides frequently could be purified already after a simple processing step. The results indicated in Table 2 have been obtained after further purification by chro a- tography. The catalytic effect of the nitrogen oxide in the experiments, as shown in Table 2, was highly satis¬ factory and surprising; for example 0.6 mmol NO resulted in 45 mmol 2-iodo-p-xylene, which corresponds to a yield of 7500% based on NO ⁺ .

The catalytic effect of NO was determined by adding decreasing amounts of NOBF. to mesitylene/NH ₄ I in

CF ₃ COOH/CH ₂ Cl ₂ . The results show that up to about 5 mol% NO should be added in small-scale experiments, and that 1-2 mol% generally are sufficient on a larger scale.

When mesitylene was iodinated on the 0.1 mol scale in CF ₃ C00H:CH_C00H in a ratio of 10:1, an extremely clean reaction was obtained, and a nearly quantitative yield of iodomesitylene could be isolated. In the same solvent system, some of the most reactive substrates could be sa¬ tisfactorily iodinated (Table 5), while toluene was con- verted in a 1:1 acid mixture. H ₂ S0 ₄ can be used in place of CF-COOH, especially with less reactive substrates.

As mentioned above, I ₂ can be used as a source of "I ". I„ was found to iodinate mesitylene one and a half to two times faster than NH ₄ I in CH ₃ COOH:CF ₃ COOH 3:1, but in the absence of CF.-C00H (i.e. in pure CH-.C00H) very large differences (about 100 g) in the reaction rate were obtained. The effect of the nitrogen oxide and the oxygen on the reaction will appear from Table 6.

Also bromination and, to some extent, chlorination of aromatic compounds can be carried out by means of the method according to the invention. Table 8 shows the re-

suits of experiments made on the basis of naphthalene and mesitylene.

According to one theory, the reaction mechanism of the method according to the invention is based on the pre- sence of a source of electrophilic iodine of low reacti¬ vity and high selectivity along the reaction path

0.5 1 ₂ + N0 ⁺ > "I ⁺ " + NO

The presence of "I " as a kinetically independent ion is possible only in strongly acidic media.

The different mechanisms behind the method according to the invention are not fully known. Nevertheless, how¬ ever, the synthetic value of the reaction is considerable- Especially by the CH ₃ C00H/NaN0 ₃ or NaN0 ₂ ~based reactions of Table 7, convenient methods of producing aryl iodides are made available, which hopefully will open up a way to their more extensive involvement in organic syntheses. Experimental Materials and methods

Dichloromethane (Merck) was dried and stored over 3A molecular sieves. Other solvents, acids and acid anhy¬ drides were of analysis quality and used directly. Stock solutions of trifluoroacetic anhydride in trifluoroacetic acid were made up to minimise handling of the former. The aromatic compounds were used either directly or after pu¬ rification by chromatography (purity > 98%). Iodine and all inorganic salts were commercial products and used di¬ rectly, as were sulphuric acid (Merck, analysis quality 95-97%), nitric acid (Merck, analysis quality, at least 65%) and fuming nitric acid (Merck, at least 96%). Solu¬ tions of dinitrogen tetroxide in dicloromethane were made up according to prior art technique.

Column chromatography was performed on 20x700 mm co- lumns on silica gel 60 (Merck, 230-400 mesh) using heptane with 0-20% chloroform as eluent. GLC analyses were performed on capillary columns (A:25 m x 0.2 mm OV1701 or

B:25 m x 0.2 mm Superox 10) with a Varian 3400 gas chro- matograph equipped with a Varian 4270 integrator, or in accordance with prior art technique.

The products were identified by comparison of GLC retention times with authentic samples, or by their mass and NMR spectra. GLC yields were determined via internal or external standard methods, using 4-bromonitrobenzene as the reference compound. General iodination procedure The aromatic compound and the iodine compound were weighed into an Erlenmeyer flask, and the solvents were added (CH ₂ C1 ₂ , when present, was added first). After flushing with 0 ₂ for 1 min, a small but constant excess pressure of 0- was maintained over the magnetically stirred reaction mixture. A few crystals of N0BF ₄ or other nitrogen oxide source were rapidly added and stirring con¬ tinued during the entire reaction time at room tempera¬ ture. In many cases, entirely colourless solutions were obtained at the end of the reaction. When the reaction was over, the reaction mixture was poured onto aqueous

Na- _j S-O /CHCl-,, whereupon the aqueous layer was washed with CHCl , and the combined organic layers were washed with water, aqueous NaHC0„, water, and then dried ( gS0 ₄ ) . After evaporation and passage through a short column, the yield was determined by GLC. Alternatively, work-up was continued by chromatography (and/or recrystallisation in some cases) as disclosed in the Tables. Special procedures Catalytic effect The catalytic effect of N0BF ₄ was determined by treating 1.5 mmol p-xylene and 1.0 mmol NH ₄ I in 10 ml CHgCOOH, 0.5 ml (CF ₃ C0) ₂ 0 and 1.0 ml CH ₂ C1 ₂ in 0 ₂ atmos¬ phere for 5 hours with 0.01-0.09 mmol N0BF ₄ . Results: mmol N0BF ₄ (% yield): 0.09 (95); 0.068 (98); 0.048 (97); 0.025 (90); 0.019 (72); 0.011 (35).

sources

The yields of iodomesitylene, determined by the above-mentioned procedure for the determination of ca¬ talytic effect, albeit with 0.08-0.10 mmol N0BF ₄ and 1.5 hours reaction time, were in the 95-100% range for NH ₄ I, Nal, KI, (n-C ₄ H _g ) ₄ NI and 1^ . Synthesis of iodomesitylene

0.11 mol mesitylene and 0.10 mol NH.I were treated with 0.001 mol N0BF ₄ in 150 ml CHgCOOH, 15 ml CF ₃ C00H and

10 ml (CH ₃ C0) ₂ 0 in 0 ₂ atmosphere at 25°C for 48 hours. At the end of the reaction and after work-up as described above, 0.095 mol iodomesitylene was obtained (yield 95% after recrystallisation in a minor amount of ethanol).

Synthesis of l-iodo-4-methoxynaphthalene A mixture of 8.2 mmol 1-methoxynaphthalene, 7.5 mmol

NH ₄ I, 30 ml CHgCOOH, 4 ml CF-.C00H and 2 ml (CH ₃ C0) ₂ 0 was stirred under 0 2, and 0.15 mmol NOBF4. was added. After

16 hours the mixture was purified, which gave 6.4 mmol (yield 85%) l-iodo-4-methoxynaphthalene; melting point (ethanol) 54-56°C.

TABLE 1. NOBF.-catalysed iodination of aromatic compounds with NH ₄ I and 0 ₂ in CF ₃ C00H/CH ₂ C1 ₂ . [ArH] = 0.050-0.057 M. [NH ₄ I]= 0.050-0.075 M. [N0BF ₄ ] = 0.005-0.010 M.-

Substrate Method— Reaction Yield of time, h Arl, % ^d ' ^e

Benzotrifluoride 140 0

Phenyl acetate 40 53

Iodobenzene A 40 92

Bromobenzene 40 87

Chlorobenzene 40 82

Fluorobenzene 40 86

Benzene 20 93 t-butylbenzene B 20 100 Toluene 20 99 p-xylene 2 100

Biphenyl 20 88 Diphenyl ether 20 91 Naphthalene 2 74 Mesitylene 2 98 Anisole 2 100

Thiophene D 2 78

1-methoxy- 2 5 naphthalene

a lodinations were carried out by adding N0BF4 to a sus- pension of NH ₄ I/ArH in CH-.C00H-/CH ₂ /C1 ₂ at room tempera¬ ture under 0., . b Containing 3-6% (CF ₃ C0) ₂ 0.

c Method A: molar ratio of ArH: H ₄ I:N0BF ₄ = 1.0,:1, 5.:0.2; 0 volume % CH ₂ C1 ₂ . Method B: 1.1:1.0:0.1; 0 volume %. Method C: 1.1:1.0:0.1; 10 volume %. Method D: 1.5:1.0:0.1; 25 volume %. d The yields were based on ArH for method A and on NH.I for methods B-D. e Determined by GLC.

TABLE 2. Preparative lodinations.—

Substrate Isolated yield.

Fluorobenzene 86 Benzene- 78

Biphenyl 90-

Diphenyl ether- 82-

Naphthalene- 93 p-xylene— 90 Mesitylene- 95-

a 20.5-25 mmol ArH, 20 mmol H ₄ I, 0.4-0.8 mmol N0BF ₄ in 60-80 ml CF ₃ C00H and 1.5-2.5 ml (CF ₃ C0) ₂ 0 under 0 ₂ at 25°C. Reaction period 50 hours; 20 hours for the two last entries. b Calculated from the total amount of iodoaromatics col¬ lected after chromatography. c 50 mmol ArH. d Air was supplied via a drying tube instead of 0 ₂ - e 10 ml CH ₂ C1 ₂ were added. f After recrystallisation (small volumes of ethanol) 83% 4-iodo-l,l'-binaphthyl, 74% 4-iododiphenyl ether and 90% iodomesitylene, respectively, were obtained.

TABLE 3. Iodination of p-xylene under varying conditions, [ArH] = 0.069 M, [NH ₄ I]= 0.063 M, [N0BF ₄ ] = 0.006 M.-

Atmosphere Yield, %- Remarks

°2 100

°2 76 No (CF ₃ C0) ₂ 0 present

Ar 0.1

°2 < 0.01 No N0BF ₄ added

Air 11 Via a drying tube

a Reactions carried out in 16 ml solvent (with/without 0.8 ml (CF ₃ CO) ₂ 0) at 25°C. Reaction period 2 hours. b Determined by GLC.

TABLE 4. Iodination of mesitylene in different solvents.

[ArH] = 0.15 M, [NH ₄ I]= 0.10 M, [ 0BF ₄ ] = 0.008-0.010 M.-

Solvent Reaction Yield, %— time, h

CH ₃ SOgH 1 100 CC1.-C00H 1 99

CFgCOOH:CHgCOOH 1:3 1 95

CH ₃ C00H 1 1

CHgCOOH 20 96

CF ₃ COOH:CH ₃ COOH 1:9 3 96 CF ₃ COOH:CH ₂ Cl ₂ 1:9 16 99

a Reaction carried out in 10 ml solvent containing 0.5 ml (CH ₃ CO) ₂ 0 at 25°C. b Determined by GLC.

TABLE 5. Iodination of aromatic compounds in CH ₃ C00H/ CF ₃ C00H and CH ₃ C00H/H ₂ S0 ₄ . [ArH] = 0.15 M, [NH.I] = 0.13 M, [N0BF ₄ ] = 0.005 M.-

Substrate Volume % CFgCOOH Reaction Yield of in CHgCOOH time, h %

Benzene 50 16 0.1

Toluene 50 16 67

Pyrene 10 70- 36 p-xylene 10 70 15

Anisole 10 20 97

1,3-dimethoxy- benzene 10 4 86

1-methoxy- naphthalene 10 4 83

Thiophene 10 1.5 gi2

Toluene 3^ 24 98

Bromobenzene c,d 48 75

a. Reaction carried out in 20 ml solvent containing 2 ml

CH ₂ C1 ₂ and 1 ml (CH ₃ C0) ₂ 0 under 0 ₂ at 25°C. b Determined by GLC. —c H2S04. instead of CF3C00H. d Solvent system: 13 ml CH ₃ C00H, 1 ml (CH ₃ C0) ₂ 0, 5 ml

^H 2 ^S0 4' ^{2 ml CH} 2 ^C1 2 ^; °" ^{8 mmo1 N0BF} 4 added. e A second addition of NOBF. was made after 30 hours. f_ Unreached ArH (60%) was detected ^" together with 3%

1-nitropyrene. j 7% 2.5-diiodothiophene were also formed.

TABLE 6. Iodination of mesitylene with I„ and NH.I. [ArH] = 0.15 M, ["I"] = 0.13 M, [N0BF ₄ ] = 0.003-0.040 M.-

Iodine [NOBF.], M Oxygen Yield, %^ source added —

0.004 Yes 100

0.004 No 23

H 0.009 No 35

0.034 No 41

0.030- No 17

0.003 Yes 98

0.003 No 0.02

0.040 No 36

0.030- No 0.3

a Reaction performed with 3 mmol mesitylene in 14 ml

CH ₃ C00H/4ml CF ₃ COOH/2ml (CH ₃ C0) ₂ 0 with 1.25 mmol I ₂ for

3 hours (the first 5 entries) or 2.50 mmol NH.I for

20 hours (the last 5 entries) at 25°C. b Reactions performed either under 0„ or in tightly stoppered flasks. c Based on "I". d Determined by GLC. e Flushed with Ar prior to addition of NOBF..

TABLE 7. Iodination of aromatic compounds with different

NOx sources

Substrate NO X sources Molar ratio Yield of

^N0 2 ^N 2°4 ^S 0.08 98

NaN0 ₂ 0.08 96

NaNO 0.08 96 v_

Mesitylene— NaN0 ₃ +NaN ₃ - 0.08 0.3

HN0„,cone. 0.08 92

HNO„, fuming 0.10 97

HN0 ₃ , fuming 1.00 79

Mesitylene— NaN0 ₃ 0.01 98^

Toluene- NaN0 ₃ 0.01 10

Toluene— NaN0 ₃ 0.01 80

a Determined by GLC, except b which refers to isolated yield. c Reaction of 3 mmol ArH, 2.5 mmol NH ₄ I in 14 ml CH ₃ C00H,

3 ml CH ₃ C00H, 2 ml CH ₂ C1 ₂ and 1 ml CH ₃ C0) ₂ 0 for 60 min in

0- atmosphere. d Reaction of 100 mmol ArH, 105 mmol Nal, 1 mmol NaN0„ in

140 ml CH ₃ C00H, 30 ml CF.-C00H, 20 ml CH ₂ C1 ₂ and 15 ml

(CH ₃ C0) ₂ 0 for 16 hours in 0 ₂ atmosphere. e As in d but with 70 ml CH ₃ C00H, 70 ml CFgCOOH for a reaction period of 120 hours. f_ As in e, but 5 ml cone H^SO. were also added. Reaction period 24 hours. g_ Added to CH C1 ₂ solution. —h Molar ratio NaN3:N0x = 1:1.

TABLE 8. NOBF.-catalysed, aramotic bromination and chlo- ritation.

5

Substrate Halogen source Yield of ArX, %—

NH.Br 98 v. ⁴

£;&- ^■ Naphthalene ² NH ₄ C1 58

.10 NH ₄ Br 97

Mesitylene- NH ₄ C1 17

a Determined by GLC. b Reaction of 2 mml ARH and 1.0 mmol NH.X and 0.1 mmol

15 N0BF ₄ in 12 ml CF ₃ COOH, 0.3 ml (CF ₃ C0) ₂ 0, 3 ml CH ₂ C1 ₂ for 20 hours in 0- atmosphere at 25°C. c Reaction of 1.5 mml ArH and 1.0 mmol NH ₄ X and 0.1 mmol N0BF ₄ in 10 ml CF ₃ C00H, 0.3 ml (CF ₃ C0) ₂ 0, 1 ml CH ₂ C1 ₂ for

2 hours in 0 ₂ atmosphere at 25°C.

20

25

30

35